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Molecular Neurobiology May 2020Mevalonate pathway inhibitors have been extensively studied for their roles in cholesterol depletion and for inhibiting the prenylation and activation of various... (Review)
Review
Mevalonate pathway inhibitors have been extensively studied for their roles in cholesterol depletion and for inhibiting the prenylation and activation of various proteins. Inhibition of protein prenylation has potential therapeutic uses against neurological disorders, like neural cancers, neurodegeneration, and neurotramatic lesions. Protection against neurodegeneration and promotion of neuronal regeneration is regulated in large part by Ras superfamily small guanosine triphosphatases (GTPases), particularly the Ras, Rho, and Rab subfamilies. These proteins are prenylated to target them to cellular membranes. Prenylation can be specifically inhibited through altering the function of enzymes of the mevalonate pathway necessary for isoprenoid production and attachment to target proteins to elicit a variety of effects on neural cells. However, this approach does not address how prenylation affects a specific protein. This review focuses on the regulation of small GTPase prenylation, the different techniques to inhibit prenylation, and how this inhibition has affected neural cell processes.
Topics: Acyl Coenzyme A; Amino Acid Motifs; Animals; Biosynthetic Pathways; Cell Membrane; Dimethylallyltranstransferase; Enzyme Activation; GTP Phosphohydrolases; Humans; Methylation; Mevalonic Acid; Nerve Tissue Proteins; Protein Binding; Protein Prenylation; Terpenes
PubMed: 31989383
DOI: 10.1007/s12035-020-01870-0 -
Archivum Immunologiae Et Therapiae... Apr 2021The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with... (Review)
Review
The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process-the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.
Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Disease Models, Animal; Gene Expression Regulation; Humans; Interferons; Microscopy, Electron; Pinus; Polyisoprenyl Phosphates; Protein Prenylation; Sterol Regulatory Element Binding Protein 2; Treatment Outcome; Viral Proteins; Virion; Virus Diseases; Virus Replication
PubMed: 33811524
DOI: 10.1007/s00005-021-00613-w -
Postepy Biochemii 2016The aim of this review is to report on influence of statins on mitochondria function. Statins are serum cholesterol-lowering drugs. They act by competitively inhibiting... (Review)
Review
The aim of this review is to report on influence of statins on mitochondria function. Statins are serum cholesterol-lowering drugs. They act by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.88), the first committed enzyme of the mevalonate pathway. In this way, statins inhibit the endogenous cholesterol synthesis. Emerging evidence suggest that statins impair mitochondria, which is demonstrated by abnormal mitochondrial morphology, decreased oxidative phosphorylation capacity and yield, decreased mitochondrial membrane potential and activation of intrinsic apoptotic pathway. Mechanisms of statin-induced mitochondrial dysfunction are not fully understood. The following causes are proposed: (i) deficiency of coenzyme Q10, an important electron carrier of mitochondrial respiratory chain; (ii) inhibition of respiratory chain complexes; (iii) inhibitory effect on protein prenylation; and (iv) induction of mitochondrial apoptosis pathway. These phenomena could play a significant role in the etiology of statin-induced disease, especially myopathy. Studies on statin-induced mitochondrial apoptosis could be useful in developing a new cancer therapy.
Topics: Apoptosis; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondria; Muscular Diseases; Oxidative Phosphorylation
PubMed: 28132458
DOI: No ID Found -
PloS One 2022Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids...
Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning-based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.
Topics: Alkyl and Aryl Transferases; Farnesyltranstransferase; Machine Learning; Protein Prenylation; Saccharomyces cerevisiae; Substrate Specificity
PubMed: 35749383
DOI: 10.1371/journal.pone.0270128 -
Chemical & Pharmaceutical Bulletin 2023Teleocidins are natural products belonging to the indole alkaloid family and show potent protein kinase C activation activity. The structural feature of teleocidins is... (Review)
Review
Teleocidins are natural products belonging to the indole alkaloid family and show potent protein kinase C activation activity. The structural feature of teleocidins is an indole-fused nine-membered lactam ring structure. Due to their unique structures and strong biological activities, many total synthesis and biosynthetic studies of teleocidins have been performed. Teleocidin biosynthesis involves interesting enzymatic reactions that are challenging in organic synthesis, including oxidative intramolecular C-N bond-forming reactions, regio- and stereo-selective reverse prenylation reactions, and methylation-triggered terpene cyclization. This review summarizes the recent research on functional and structural analyses, as well as enzyme engineering, of teleocidin biosynthetic enzymes.
Topics: Cyclization; Lyngbya Toxins; Phosphorylation; Prenylation; Protein Kinase C
PubMed: 36858523
DOI: 10.1248/cpb.c22-00849 -
MBio Aug 2023In the apicomplexans, endocytosed cargos (e.g., hemoglobin) are trafficked to a specialized organelle for digestion. This follows a unique endocytotic process at the...
In the apicomplexans, endocytosed cargos (e.g., hemoglobin) are trafficked to a specialized organelle for digestion. This follows a unique endocytotic process at the micropore/cytostome in these parasites. However, the mechanism underlying endocytic trafficking remains elusive, due to the repurposing of classical endocytic proteins for the biogenesis of apical organelles. To resolve this issue, we have exploited the genetic tractability of the model apicomplexan , which ingests host cytosolic materials (e.g., green fluorescent protein[GFP]). We determined an association between protein prenylation and endocytic trafficking, and using an alkyne-labeled click chemistry approach, the prenylated proteome was characterized. Genome editing, using clustered regularly interspaced short palindromic repaet/CRISPR-associated nuclease 9 (CRISPR/Cas9), was efficiently utilized to generate genetically modified lines for the functional screening of 23 prenylated candidates. This identified four of these proteins that regulate the trafficking of endocytosed GFP vesicles. Among these proteins, Rab1B and YKT6.1 are highly conserved but are non-classical endocytic proteins in eukaryotes. Confocal imaging analysis showed that Rab1B and Ras are substantially localized to both the trans-Golgi network and the endosome-like compartments in the parasite. Conditional knockdown of Rab1B caused a rapid defect in secretory trafficking to the rhoptry bulb, suggesting a trafficking intersection role for the key regulator Rab1B. Further experiments confirmed a critical role for protein prenylation in regulating the stability/activity of these proteins (i.e., Rab1B and YKT6.1) in the parasite. Our findings define the molecular basis of endocytic trafficking and reveal a potential intersection function of Rab1B on membrane trafficking in . This might extend to other related protists, including the malarial parasites. IMPORTANCE The protozoan establishes a permissive niche, in host cells, that allows parasites to acquire large molecules such as proteins. Numerous studies have demonstrated that the parasite repurposes the classical endocytic components for secretory sorting to the apical organelles, leaving the question of endocytic transport to the lysosome-like compartment unclear. Recent studies indicated that endocytic trafficking is likely to associate with protein prenylation in malarial parasites. This information promoted us to examine this association in the model apicomplexan and to identify the key components of the prenylated proteome that are involved. By exploiting the genetic tractability of and a host GFP acquisition assay, we reveal four non-classical endocytic proteins that regulate the transport of endocytosed cargos (e.g., GFP) in . Thus, we extend the principle that protein prenylation regulates endocytic trafficking and elucidate the process of non-classical endocytosis in and potentially in other related protists.
Topics: Toxoplasma; Proteome; Protozoan Proteins; Protein Transport; Endosomes; Green Fluorescent Proteins
PubMed: 37548452
DOI: 10.1128/mbio.01309-23 -
Proteomics Mar 2016Covalent lipid modifications of proteins are crucial for regulation of cellular plasticity, since they affect the chemical and physical properties and therefore protein... (Review)
Review
Covalent lipid modifications of proteins are crucial for regulation of cellular plasticity, since they affect the chemical and physical properties and therefore protein activity, localization, and stability. Most recently, lipid modifications on proteins are increasingly attracting important regulatory entities in diverse signaling events and diseases. In all cases, the lipid moiety of modified proteins is essential to allow water-soluble proteins to strongly interact with membranes or to induce structural changes in proteins that are critical for elemental processes such as respiration, transport, signal transduction, and motility. Until now, roughly about ten lipid modifications on different amino acid residues are described at the UniProtKB database and even well-known modifications are underrepresented. Thus, it is of fundamental importance to develop a better understanding of this emerging and so far under-investigated type of protein modification. Therefore, this review aims to give a comprehensive and detailed overview about enzymatic and nonenzymatic lipidation events, will report their role in cellular biology, discuss their relevancy for diseases, and describe so far available bioanalytical strategies to analyze this highly challenging type of modification.
Topics: Humans; Lipid Metabolism; Lipids; Lipoylation; Protein Prenylation; Proteins
PubMed: 26683279
DOI: 10.1002/pmic.201500353 -
The Journal of Steroid Biochemistry and... Jul 2019Cholesterol is essential for maintaining membrane fluidity in eukaryotes. Additionally, the synthetic cascade of cholesterol results in precursor molecules important for... (Review)
Review
Cholesterol is essential for maintaining membrane fluidity in eukaryotes. Additionally, the synthetic cascade of cholesterol results in precursor molecules important for cellular function such as lipid raft formation and protein prenylation. As such, cholesterol homeostasis is tightly regulated. Interestingly, it is now known that some cholesterol precursors and many metabolites serve as active signaling molecules, binding to different classes of receptors including the nuclear receptors. Furthermore, many cholesterol metabolites or their nuclear receptors have been implicated in the regulation of the immune system in normal physiology and disease. Therefore, in this focused review, cholesterol homeostasis and nuclear receptors involved in this regulation will be discussed, with particular emphasis on how these cascades influence the immune system.
Topics: Animals; Cholesterol; Homeostasis; Humans; Immune System; Immunity; Receptors, Cytoplasmic and Nuclear
PubMed: 31002862
DOI: 10.1016/j.jsbmb.2019.04.013 -
Nature Methods Jun 2019
Topics: Protein Prenylation
PubMed: 31147650
DOI: 10.1038/s41592-019-0446-3 -
Frontiers in Immunology 2021Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear... (Review)
Review
Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
Topics: Biosynthetic Pathways; Genetic Association Studies; Humans; Immunotherapy; Inflammation; Mevalonate Kinase Deficiency; Protein Prenylation; Terpenes
PubMed: 34539662
DOI: 10.3389/fimmu.2021.724991